mid2163 topic 3

TOPIC 3:TOPIC 3:INFLAMMATIONINFLAMMATION

OBJECTIVES

Causes of inflammation Inflammation classifications

– Acute Inflammation– Chronic Inflammation

Systemic effects of inflammation

INFLAMMATION

Latin word, 'inflammare' = to burn Body's response to injury

DEFINITION:

− Local defence mechanism initiated by tissue injury

INFLAMMATION

Physiological response to tissue damage & accompanied by a characteristic series of local changes– Inflammatory reaction takes place in the

surviving adjacent vascular & connective tissues

INFLAMMATION

Purpose: Protection⇨to localize & isolate toxic substances⇨remove/destroy the injurious stimuli

(pathogens) and damaged tissue⇨initiate the healing and repair process –

remove the cellular debris from the area

NOMENCLATURE

Inflammatory lesion are usually indicated by the suffix ~'itis'

Example:⇨Appendicitis = inflammation of the appendix

⇨Meningitis = inflammation of the meninges

Some exceptions, example: pneumonia, typhoid fever

CAUSES

Physical agents→Mechanical injuries, alteration of temperature &

pressure, radiation injuries, ultraviolet

Chemical agents→Organic – microbial toxins & organic poisons

(weedkillers)

→ Inorganic – acids, alkaline, drugs

Biological agents/microbes→ Infectious = bacteria, viruses, fungi, protozoa

CAUSES

Immunologic disorders→Hypersensitivity reactions, autoimmunity,

immunodificiency states

Genetic/metabolic disorders→ Gout, diabetes mellitus

Antigens that stimulate immunological response

CLASSIFICATIONS

CLASSIFICATION

Based on duration of the lesion and histologic appearances

2 classifications⇨Acute inflammation⇨Chronic inflammation

ACUTE INFLAMMATION

ACUTE INFLAMMATION

Immediate & early response to an injurious agent = protective response!

→Early vascular response and late cell response

Relatively non-specific response

→eliminate dead tissue, protect against local infection & allows immune system to response = beneficial

ACUTE INFLAMMATION

Relatively short duration

→ lasting for minutes, several hours of a few days

→ may range from normal to severe

ACUTE INFLAMMATION

5 cardinal signs

1)Rubor

2)Calor

3)Tumor

4)Dolor

5)Functio laesa- latin words

ACUTE iNFLAMMATION

1) Rubor Redness Due to dilation of small blood vessels within

damaged tissue as it occurs in cellulitis by the action of mediators

*cellulitis: inflammation spread to the connective tissue

ACUTE iNFLAMMATION

2) Calor Heat Results from increased blood flow

(hyperemia) due to: regional vascular dilation cellular metabolism

ACUTE iNFLAMMATION

3) Tumor Swelling Due to accumulation of fluid in the

extravascular space = increased vascular permeability

ACUTE iNFLAMMATION

4) Dolor Pain Partly results from the stretching &

destruction of tissues due to inflammatory edema & part from pus under pressure in as abcess cavity

Some chemicals of acute inflammation are also known to induce pain Bradykinins, prostaglandin & serotonin

ACUTE iNFLAMMATION

5) Functio leasa Loss of function Inflamed area is inhibited by pain while

severe swelling may also physically immobilize the tissue

Steps of Acute Inflammation

Steps of acute inflammation

1) Increased blood flow = hyperemia

2) Exudation of fluids & plasma proteins Exudate: discharge of fluid or substances from cells

or blood vessels onto the skin or organ surface

3) Emigration of leucocytes

Capillaries become engorged & dilated with blood (congestion)

Leakage of fluids and protein into the tissues = infiltration of leukocytes into the

area of injury

Leukocytes engulf and digest the pathogens and help remove it from the area

(phagocytosis)

1) Hyperemia

(a) Injured tissues by any agents

(b) Following injury, both the arterioles supplying the damaged area and local capillaries dilate – increasing blood flow to the site

• this causes redness (rubor) & increased heat (calor) in the affected region

1) Hyperemia

Caused mainly by local released of a number of chemical mediators from damaged cells

Mast cells release histamine in response to tissue injury or infection

INJURY

Damaged Cells

CHEMICAL MEDIATORS

VASCULAR DILATATION

Direct effect on vessels

Nervous reaction (axon reflex)

2) Exudation of Fluids

* Exudation: increased passage of protein-rich fluid through the vessel wall into the interstitial tissue

Fluid leaving local blood vessels & entering interstitial space = swelling / oedema

Caused by → Increased permeability of small blood

vessels wall

→ Increased hydrostatic pressure


INCREASED PERMEABILITY

Caused by→ inflammatory mediators released by

injured cells– prostaglandin, histamine & serotonin

→ cells that formed the single-layered venules pull apart from one another


INCREASED PERMEABILITY

The opening of channels that allow the movement of→ Excess fluid = leaves blood & enters

tissues

→ Plasma proteins =albumin, globulin etc – normally retained in bloodstream reduced osmotic pressure of blood


INCREASED HYDROSTATIC PRESSURE Increased blood flow into the capillary bed

forces fluid out of the vessels & into the tissues

Some interstitial fluid returns to capillaries but most of the inflammatory exudates, phagocytes & cell debris removed in lymph vessels

→ pores of the lymph vessels larger & pressure inside it is lower than blood capillaries

3) Emigration of Leukocytes

Loss of fluid→ thicken the blood

→ reduced the flow

→ allowing leukocytes make contact & adhere to the vessel wall = selectin & integrins


Most important leukocyte = neutrophil→ Adhere to the blood vessels lining

→ Squeeze between endothelial cells

→ Enters tissue and went to the inflamed area by chemotaxis

→ Main function: phagocytosis of antigen


Macrophages→ larger and longer lived than neutrophils

→ phagocytose dead/dying tissue, microbes & other antigenic material and dead/dying neutrophils

→ predominently in inflamed tissue after 24hours

→ persist in the tissue if the situation is not resolved = chronic inflammation

CHEMOTAXIS Movement of a motile cell/organism in a direction corresponding to a gradient of increasing or decreasing concentration of the particular chemotactic agent– Chemical attraction of leukocytes to an area of

inflammation

PHAGOCYTOSISCell eatingMacrophages & neutrophils attracted to the inflammatory & infectious site by chemotaxisChemo-attractans released by injured cells & invading microbesPhagocytes trap particles either by engulfing them with their body mass or by extending long psedopodia towards themNon-selective = bind, engulf and digest foreign cells or particles

CHEMICAL MEDIATORS Various chemical mediators have roles in inflammatory process They may be circulating in plasma and require activation or may be secreted by inflammatory cells

Mast cells = histamine Platelets = serotonin

Many of these mediators have overlapping actions

Vasodilating chemicals

Histamine, serotonin, bradykinins, prostaglandin

Chemotactic factors

Fibrin, collagen, mast cell, bacterial peptides

Substances with both vasodilating & chemotactic effects

Complement fragments of C5a and C3a, interferons, interleukines and platelet secretion

Chemical mediators of Inflammation

Morphology of Acute Inflammation

MORPHOLOGY

Involves production of exudates (edema fluid with high protein concentration, frquently contain inflammatory cells)

*Transudate? Non-inflammatory edema

Caused by cardiac, renal, undernutritional and other disorders

MORPHOLOGY

Different morphologic types of accute inflammationi. Serous inflammation - watery

ii. Fibrinous inflammation - haemorrhagic

iii.Suppurative (purulent) inflammation - pus

iv.Catharral inflammation – mucous membrane

v. Pseudomembranous inflammation

BLISTER, “Watery”, i.e., SEROUS

i. Serous Inflammation

Characterized by an outpouring of a thin fluid that is derived from either the blood serum or secretion of mesothelial cells lining the peritoneal, pleural, and pericardial cavities

It resolves without reactions

FIBRINOUS

ii. Fibrinous Inflammation More severe injuries Result in greater vascular permeability that

ultimately leads to exudation of larger molecules such as fibrinogens through the vascular barrier

Fibrinous exudate is characteristic of inflammation in serous body cavities such as the pericardium (butter and bread appearance) and pleura

ii. Fibrinous Inflammation

Course of fibrous inflammation include:– Resolution by fibrinolysis– Scar formation between perietal and

visceral surfaces i.e. the exudates get organized

– Fibrous strand formation that bridges the pericardial space

PUS

=

PURULENT

ABSCESS

=

POCKET

OF

PUS

iii. Suppurative Inflammation

Characterized by the production of a large amount of pus– Pus is a thick creamy liquid, yellowish or

blood stained in colour and composed of• A large number of living or dead

leukocytes (pus cells)• Necrotic tissue debris• Living and dead bacteria• Edema fluid


2 types:

A) Abscess formation:– abscess = a circumscribed accumulation of pus

in a living tissue

– encapsulated by a so-called pyogenic membrane, which consists of layers of fibrin, inflammatory cells and granulation tissue


2 types:

B) Acute diffuse (phlegmonous) inflammation– characterized by diffuse spread of the exudate

through tissue spaces

– caused by virulent bacteria (eg. streptococci) without either localization or marked pus formation

– example: Cellulitis (in palmar spaces)

iv. Catharral Inflammation

Mild and superficial inflammation of the mucous membrane

Commonly seen in the upper respiratory tract following viral infections where mucous secreting glands are present in large numbers

example: Rhinitis.

v. Pseudomembranous Inflammation

Basic elements – extensive confluent necrosis of the

surface epithelium of an inflamed mucosa – severe acute inflammation of the

underlying tissues The fibrinogens in the inflamed tissue

coagulate within the necrotic epithelium

v. Pseudomembranous Inflammation

Fibrinogen, necrotic epithelium, neutrophilic polymorphs, red blood cells, bacteria and tissue debris form a false (pseudo) membrane = forms a white or colored layer over the surface of inflamed mucosa

Example:– Dipthetric infection of the pharynx or larynx

– Clostridium difficille infection in the large bowel following certain antibiotic use

Effects of Acute Inflammation

EFFECTS

2 types of effects

(a) Beneficial effects

(b) Harmful effects

BENEFICIAL EFFECTS

a) Dilution of toxins:

►concentration of chemical and bacterial toxins at the site of inflammation reduced by dilution in the exudate

►removal from the site by the flow of exudates from the venules through the tissue to the lymphatic

BENEFICIAL EFFECTS

b) Protective antibodies:

►Formation of tissue exudation allows protective proteins including antibodies at the site of inflammation

►Thus, antibodies promote microbial destruction by phagocytosis or complement-mediated cell lysis = neutralise their toxins

BENEFICIAL EFFECTS(c)Fibrin formation:

– Tissue damage is repaired and scars can form if fibroblasts are involved.

BENEFICIAL EFFECTS

d) Promotion of phagocytosis►Neutrophils & macrophages actively

recruited to the inflamed areas = engulf biological & non-biological origin

►Phagocyte activity promoted by increasing temperature (local & systemic)

►Phagocytes may die at the inflamed area if the material they ingest resist digestion or excessive = disintegrate & released material that cause further damage

BENEFICIAL EFFECTS

e) Cell nutrition: ►The flow of inflammatory exudates brings

with it glucose, oxygen and other nutrients to meet the metabolic requirements of the greatly increased number of cells

►It also removes their solute waste products via lymphatic channels

BENEFICIAL EFFECTS

f) Promotion of immunity: ►Micro-organisms and their toxins are carried

by the exudates, either free or in phagocytes, along the lymphatics to local lymph nodes

• they stimulate an immune response with the generation of antibodies and cellular immune mechanisms of defence

HARMFUL EFFECTS

Tissue swelling⇨Result of the increased blood flow &

exudation⇨Often accompanies by loss of function⇨Effects can be harmful = depending on the

site• Joint = limitation of movement• Larynx = interference with breathing

HARMFUL EFFECTS

Pain⇨Occurs when local swelling compress

sensory nerve endings⇨Exacerbated by chemical mediators of the

inflammatory process that potentiate the sensitivity of the sensory nerve endings

• Bradykinin• Prostaglandin

Course of Acute Inflammation

COURSE OF ACUTE INFLAMMATION

possible outcomes depend on removal of inflammatory exudate and replacement by either regenerated cells or scar tissue 4 possible outcomes

(1) Resolution

(2) Healing by fibrosis

(3) Abscess formation

(4) Chronic inflammation

COURSE OF ACUTE INFLAMMATION

Factors affecting outcome of acute inflammation

(1) severity of tissue damage

(2) capacity of stem cells to divide

(3) type of agent causing damage

(1)Resolution

involves complete restitution of normal architecture and function 3 main features which potentiate this sequel are

→ Minimal cell death & tissue damage

→ Rapid elimination of the causal agent

→ Local conditions favouring of fluid & debris

(1)Resolution

Inflammatory process is reversed and→ damaged cells are phagocytosed

→ fibrin strands are broken down by fibrinolytic enzymes

→ waste material is removed in lymph and blood vessels

→ repair is complete leaving only a small car

(1)Resolution

Arises from damage to parenchyma in labile/stable tissues

cells replaced by regeneration normal function restored

Can only occur if the connective tissue framework of the tissue is intact & the tissue involved has the capacity to replace any specialised cells that have been lost

(2)Healing by Fibrosis Occurs when

connective tissue framework damage tissue lacks the ability to regenerate

specialised cells 1St: dead tissues & acute inflammatory exudate removed by macrophages Defect filled by ingrowth of a specialised vascular connective tissue called granulation tissue

(2)Healing by Fibrosis granulation tissue - gradually produces collagen = form a fibrous (collagenous) scar = repair loss of some specialised cells & some architectural distortion by fibrous scar = structural integrity is re-established any impairment of function = dependent on the extent of loss of specialised cells

(2)Healing by Fibrosis Modified forms of repair occur in

► bone after a fracture when new bone is created

► brain with the formation of an astrocytic scar

(3)Abscess Formation Takes place when

acute inflammatory reaction fails to destroy/remove the cause of tissue damage

continues with a component of chronic inflammation

Most common: infection by pyogenic bacteria As the acute inflammation progresses, there is liquefaction of the tissue to form pus Peripherally, a chronic inflammatory component & fibrous tissue surrounds the area = localising puss

(3)Abscess Formation If abscess left untreated, it can lead to

sinus formation fistula formation

(3)Abscess FormationSinus

tract lined by granulation tissue leading from a chronically inflamed cavity

to a surface cause the continuing presence of foreign or

necrotic material Example: sinus associated with

osteomyelitis & pilonidal sinus

A pilonidal dimple is a small pit or sinus in the sacral area just at the top of the crease between the buttocks - deep tract, rather than a shallow depression, leading to a sinus that may contain hair. During adolescence the pilonidal dimple or tract may become infected forming a cyst-like structure called a pilonidal cyst = may require surgical drainage or total excision to prevent reinfection

(3)Abscess FormationFistula

tract open at both ends Abnormal communication b etween two

surfaces is established 2 main types

congenital = development abnormality acquired = trauma, inflammation or necrosis

(4)Chronic Inflammation May result following acute inflammation when an injurious agent persists over a prolonged period Causing concomitant tissue destruction, inflammation, organisation and repair Some injurious agents induced a chronic inflammatory type of response from the outset

CHRONIC INFLAMMATION

CHRONIC INFLAMMATIONprolonged inflammatory process (weeks or months) where an active

inflammation, tissue destruction and attempts at repair are proceeding

simultaneously

Causes

Persistent infections

→Certain microorganisms associated with intracellular infection = tuberculosis, leprosy, certain fungi characterictically cause chronic inflammation

→These organisms have low tosicity and evoke delayed hypersensitivity reactions

Causes

Prolonged exposure to nondegradable but partially toxic substances

→endogenous lipid components which result in atherosclerosis

→exogenous substances such as silica, asbestos

Causes

Progression from acute inflammation

→acute inflammation almost always progresses to chronic inflammation following persistent suppuration as a result of

• uncollapsed abscess cavities• foreign body materials (dirt, cloth, wool,

etc)• sequesterum in osteomylitis• sinus/fistula from chronic abscesses

Causes

Autoimmunity

→autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosis are chronic inflammations from the outset

Morphology

Cells of chronic inflammation– Monocytes & macrophages = main

cells– T-lymphocytes– B-lymphocytes & plasma

Classification

Classified into 2 types based on histologic features

1. Non-specific chronic inflammation2. Specific inflammation

(granulomatous inflammation)

Classification

1. Non-specific chronic inflammation– involves a diffuse accumulation of

macrophages and lymphocytes at site of injury that is usually productive with new fibrous tissue formations

– example: Chronic cholecystitis.

Classification

2. Specific inflammation– Granulomatous inflammation– characterized by the presence of

granuloma• granuloma is a microscopic aggregate of

epithelioid cells (modified macrophages)

Classification

2. Specific inflammation– Epithelioid cell

• is an activated macrophage, with a modified epithelial cell-like appearance (hence the name epithelioid)

• can fuse with each other & form multinucleated giant cells – foreign body-type giant cells & Langhans giant cells

Classification

2. Specific inflammation– granuloma is basically a collection of

epithelioid cells, it also usually contains multinucleated giant cell & is usually surrounded by a cuff of lymphocytes and occasional plasma cells

Pathogenesis

2 types of granuloma

1. Foreign body granuloma2. Immune granuloma

Pathogenesis

1.Foreign body granuloma– initiated by inert foreign bodies such as

talc, sutures (nonabsorbable), fibers, etc…– these foreign bodies are large enough to

preclude phagocytosis by a single macrophage and do not incite an immune response

Pathogenesis

2.Immune granulomas– antigen presenting cells (macrophages) engulf a

poorly soluble inciting agent

– then, the macrophage processes and presents part of the antigen and activated lymphocytes

– the activated lymphocytes produce cytokines that activate another lymphocytes = transform macrophages into epitheloid & multinucleated giant cells & maintain the granuloma

– Macrophage inhibitory factor helps to localize activated macrophages & epitheloid cells

Causes Major causes of granulomatious inflammation:

– Bacterial: Tuberculosis, Leprosy, Syphilis, Cat scratch disease, Yersiniosis

– Fungal: Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Blastomycosis

– Helminthic: Schistosomiasis

– Protozoal: Leishmaniasis, Toxoplasmosis

– Chlamydia: Lymphogranuloma venerum

– Inorganic material: Berrylliosis

– Idiopathic: Acidosis, Cohn’s disease, Primary biliary cirrhosis

SYSTEMIC EFFECTS OF INFLAMMATION

Systemic effects of Inflammation

Include 1. Fever

2. Endocrine & metabolic responses

3. Autonomic responses

4. Behavioural responses

5. Leukocytosis

6. Leukopenia

7. Weight loss

1.Fever most important systemic manifestation of

inflammation. It is coordinated by the hypothalamus & by cytokines released from macrophages and other cells

2. Endocrine & metabolic responses the liver secrets acute phase proteins such as C-

reactive proteins, Serum Amyloid A, complement and coagulation proteins

Glucocorticoids (increased) Vasopressin (decreased)

3. Autonomic responses redirection of blood flow from the cutaneous to

the deep vascular bed pulse rate and blood pressure (increased) sweating (decreased)

4. Behavioural responses Rigor, chills, anoroxia, somnolence and malaise

5. Leukocytosis also a common feature of inflammation,

especially in bacterial infections its usual count is 15,000 to 20,000 cells/mm3 most bacterial infections induce neutrophilia some viral infections such as infectious

mononucleosis, & mumps cause lymphocytosis parasitic infestations & allergic reactions such

as bronchial ashma & hay fever induce eosinophilia

6. Leukopenia Also a feature of thyphoid fever and some

parasitic infections

7. Weight loss Catabolism of skeletal muscle, adipose tissue

and the liver with resultant negative nitrogen balance

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